Autoimmune diseases (AIDs) refer to a class of diseases in which autoimmune tolerance is disrupted, and the immune system is activated to attack self-antigens, leading to damage of tissues or organs. AIDs currently are considered as hypersensitivity diseases against self-antigens caused by autoantibodies, auto-reactive T lymphocytes or both. AIDs can be divided into two categories, i.e., organ-specific AIDs and systemic AIDs. The organ-specific autoimmune diseases refer to diseases in which the pathological damage and dysfunction of a tissue or organ are only limited to the organ to which the antibody or sensitized lymphocyte is directed, and examples of which mainly include Hashimoto's thyroiditis, toxic diffuse goiter, insulin-dependent diabetes mellitus, myasthenia gravis, autoimmune thrombocytopenic purpura, autoimmune hemolytic anemia, pernicious anemia, Goodpasture's syndrome, pemphigus vulgaris, etc. The systemic autoimmune diseases refer to damages to multiple organs in the whole body due to, for example, the wide deposition of an antigen-antibody complex in the blood vessel wall, including systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, cryoglobulinemia, multiple sclerosis, etc.
There has been no cure for AIDs. Although traditional glucocorticoids and immunosuppressive agents can control the disease and improve the survival rate of patients when administered timely, long-term use thereof brings about a series of side effects, which can affect the life quality of patients, or even can be life-threatening in severe cases. Moreover, some patients may be insensitive to the treatments with glucocorticoids and immunosuppressive agents. In recent years, new therapeutic strategies have been proposed, including gene therapy, epigenetic intervention, a small molecule Toll-like receptor inhibitor, an anti-inflammatory factor antibody, B-cell depletion, autotransfusion of stem cells and regulatory T cells, a dendritic cell vaccine, etc. Some of these therapeutic drugs or methods have been used clinically (such as belimumab, rituximab, etc.), and some are still under clinical research (such as stem cell autotransfusion therapy, and the like), or even at the stage of animal testing (such as epigenetic regulation, and the like). However, these drugs cannot replace glucocorticoids as first-line drugs. Thus there exist a pressing need for alternative effective therapeutic drugs and methods for clinical application.
Brain-derived neurotrophic factor (BDNF) of a molecular weight of 12.4 kDa is a neurotrophic factor found after the discovery of the nerve growth factor. It is mainly distributed in the central nervous system, but is also in the peripheral nervous system. BDNF has important functions in the regulation of neuronal survival, differentiation, synaptic plasticity, damage repair, etc. Currently, there is evidence that BDNF is not only an important factor in the regulation of nervous system development and affective disorder, but also an important pain modulator.
The precursor of brain-derived neurotrophic factor (proBDNF) is synthesized in the endoplasmic reticulum through transcription and translation from the BDNF gene. The resulting peptide chain has 247 amino acids. Its amino acid sequence has a theoretical molecular weight of 27.8 kD, but the actual molecular weight can vary in the range of 32-36 kD due to different degrees of protein glycosylation modification. A signal peptide sequence is located at positions 1-18 of the amino acid sequence of proBDNF. Two fragments are produced during protein secretion: a polypeptide fragment (known as proBDNF pro-domain) comprising amino acids 19-129 of the sequence, i.e., a precursor domain; and a fragment encoded by amino acids 130-247 of the sequence, i.e., a mature domain, which fragment forms a mature BDNF with bioactivity after being processed.
Currently, there is considerable evidence that proBDNF not only acts as an intermediate for the synthesis of mature BDNF, but also can be used as a ligand that mediates biological effects in conjunction with its high affinity receptor p75 neurotrophin receptor (p75NTR). Researches show that precursors of neurotrophic factor (including proNGF, proBDNF, etc.) can promote apoptosis and inflammatory responses. However, the roles of proBDNF and its signaling in autoimmune diseases has not been reported.